tbuckley/cabot-search huggingface dataset:
HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway by regulating MSK1 and PPP2R2B
Authors: Parmanand Malvi, Suresh Chava, Guoping Cai, Kai Hu, Lihua Julie Zhu, Yvonne J.K. Edwards, Michael R. Green, Romi Gupta, Narendra Wajapeyee
Journal: Cell Reports Medicine (2023)

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. Here, we demonstrate that the transcription factor, homeobox C6 (HOXC6), is overexpressed in most PDACs, and its inhibition blocks PDAC tumor growth and metastasis. HOXC6 transcriptionally activates tumor-promoting kinase MSK1 and suppresses tumor-inhibitory protein PPP2R2B in PDAC. HOXC6-induced PPP2R2B suppression causes mammalian target of rapamycin (mTOR) pathway activation, which facilitates PDAC growth. Also, MSK1 upregulation by HOXC6 is necessary for PDAC growth because of its ability to suppress apoptosis via its substrate DDX17. Combinatorial pharmacological inhibition of MSK1 and mTOR potently suppressed PDAC tumor growth and metastasis in PDAC mouse models. PDAC cells with acquired resistance to MSK1/mTOR-inhibitors displayed activated insulin-like growth factor 1 receptor (IGF1R) signaling and were successfully eradicated by IGF1R inhibitor. Furthermore, MEK inhibitor trametinib enhanced the efficacy of dual MSK1 and mTOR inhibition. Collectively, these results identify therapeutic vulnerabilities of PDAC and an approach to overcome acquired drug resistance to prolong therapeutic benefit.
Travel Time and Costs for Abortion for Military Service Members After the <i>Dobbs</i> Decision
Authors: Benjamin Rader, Yulin Hswen, Neil K. R. Sehgal, John S. Brownstein
Journal: JAMA (2023)

This study quantifies the change in travel times for military service personnel to abortion facilities following the US Supreme Court Dobbs decision and estimates the cost of an abortion-related travel reimbursement policy.
Is Nosocomial SARS-CoV-2 Still Worth Preventing?
Authors: Michael Klompas, Meghan A. Baker, Chanu Rhee
Journal: JAMA Network Open (2023)

Nishi Dave, MSc; Daniel Sjöholm, MSc; Pontus Hedberg, MD, PhD; Anders Ternhag, MD, PhD; Fredrik Granath, PhD; Janneke D. M. Verberk, PhD; Anders F. Johansson, MD, PhD; Suzanne D. van der Werff, PhD; Pontus Nauclér, MD, PhD
mRNA SARS-CoV-2 Vaccination Before vs During Pregnancy and Omicron Infection Among Infants
Authors: Orlanda Goh, Deanette Pang, Janice Tan, David Lye, Chia Yin Chong, Benjamin Ong, Kelvin Bryan Tan, Chee Fu Yung
Journal: JAMA Network Open (2023)

Infants younger than 6 months are at risk of severe SARS-CoV-2 infection. Data are lacking on the optimum timing for maternal vaccination and estimated effectiveness against Omicron variants, including XBB, for infants.
A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment
Authors: Jun Long, Xinjie Chen, Yan Shen, Yichen Lei, Lili Mu, Zhen Wang, Rufang Xiang, Wenhui Gao, Lining Wang, Ling Wang, Jieling Jiang, Wenjun Zhang, Huina Lu, Yan Dong, Yi Ding, Honghu Zhu, Dengli Hong, Yi Eve Sun, Jiong Hu, Aibin Liang
Journal: Cell Reports Medicine (2023)

<h2>Summary</h2> Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%–30% of patients with acute myeloid leukemia (AML) and are associated with dismal prognosis. Although FLT3 inhibitors have demonstrated initial clinical efficacy, the overall outcome of patients with FLT3-ITD AML remains poor, highlighting the urgency to develop more effective treatment strategies. In this study, we reveal that FLT3 inhibitors reduced protein stability of the anti-cancer protein p53, resulting in drug resistance. Blocking p53 degradation with proteasome inhibitors restores intracellular p53 protein levels and, in combination with FLT3-ITD inhibitors, shows superior therapeutic effects against FLT3-ITD AML in cells, mouse models, and patients. These data suggest that this combinatorial therapeutic approach may represent a promising strategy to target FLT3-ITD AML.
Misgendering and the health and wellbeing of nonbinary people in Canada
Authors: Kai Jacobsen, Charlie E. Davis, Drew Burchell, Leo Rutherford, Nathan Lachowsky, Greta Bauer, Ayden Scheim
Journal: International Journal of Transgender Health (2023)

Misgendering-using the wrong name, pronoun, or gendered language to refer to someone-is known to have negative impacts on the mental health and well-being of trans individuals generally. However, little is known about the effects of misgendering on nonbinary people specifically.
Evaluation of deep learning-based feature selection for single-cell RNA sequencing data analysis
Authors: Hao Huang, Chunlei Liu, Manoj M Wagle, Pengyi Yang
Journal: Genome biology (2023)

Feature selection is an essential task in single-cell RNA-seq (scRNA-seq) data analysis and can be critical for gene dimension reduction and downstream analyses, such as gene marker identification and cell type classification. Most popular methods for feature selection from scRNA-seq data are based on the concept of differential distribution wherein a statistical model is used to detect changes in gene expression among cell types. Recent development of deep learning-based feature selection methods provides an alternative approach compared to traditional differential distribution-based methods in that the importance of a gene is determined by neural networks.
Diverse biological functions of the renin‐angiotensin system
Authors: Adithi Rao, Shabir A. Bhat, Tomohiro Shibata, Jorge F. Giani, Florian Rader, Kenneth E. Bernstein, Zakir Khan
Journal: Medicinal Research Reviews (2023)

Abstract The renin‐angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS‐inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.
Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells
Authors: Kevin W Southerland, Yueyuan Xu, Derek T Peters, Xin Lin, Xiaolin Wei, Yu Xiang, Kaileen Fei, Lindsey A Olivere, Jeremy M Morowitz, James Otto, Qunsheng Dai, Christopher D Kontos, Yarui Diao
Journal: Genome Medicine (2023)

Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15-20% and substantial mortality. A key feature of CLTI is the compromised regenerative ability of skeletal muscle; however, the mechanisms responsible for this impairment are not yet fully understood. In this study, we aim to delineate pathological changes at both the cellular and transcriptomic levels, as well as in cell-cell signaling pathways, associated with compromised muscle regeneration in limb ischemia in both human tissue samples and murine models of CLTI.
Peptide Amphiphiles as Biodegradable Adjuvants for Efficient Retroviral Gene Delivery
Authors: Kübra Kaygisiz, Lena Rauch‐Wirth, Aysenur Iscen, Jan Hartenfels, Kurt Kremer, Jan Münch, Christopher V. Synatschke, Tanja Weil
Journal: Advanced Healthcare Materials (2023)

Abstract Retroviral gene delivery is the key technique for in vitro and ex vivo gene therapy. However, inefficient virion‐cell attachment resulting in low gene transduction efficacy remains a major challenge in clinical applications. Adjuvants for ex vivo therapy settings need to increase transduction efficiency while being easily removed or degraded post‐transduction to prevent the risk of venous embolism after infusing the transduced cells back to the bloodstream of patients, yet no such peptide system have been reported thus far. In this study, peptide amphiphiles (PAs) with a hydrophobic fatty acid and a hydrophilic peptide moiety that reveal enhanced viral transduction efficiency are introduced. The PAs form β‐sheet‐rich fibrils that assemble into positively charged aggregates, promoting virus adhesion to the cell membrane. The block‐type amphiphilic sequence arrangement in the PAs ensures efficient cell‐virus interaction and biodegradability. Good biodegradability is observed for fibrils forming small aggregates and it is shown that via molecular dynamics simulations, the fibril‐fibril interactions of PAs are governed by fibril surface hydrophobicity. These findings establish PAs as additives in retroviral gene transfer, rivalling commercially available transduction enhancers in efficiency and degradability with promising translational options in clinical gene therapy applications.
Prospective Evaluation of High Titer Autoantibodies and Fetal Home Monitoring in the Detection of Atrioventricular Block Among Anti‐SSA/Ro Pregnancies
Authors: Jill. P. Buyon, Mala Masson, Caroline G. Izmirly, Colin Phoon, Ruben Acherman, Elena Sinkovskaya, Alfred Abuhamad, Majd Makhoul, Gary Satou, Whitnee Hogan, Nelangi Pinto, Anita Moon‐Grady, Lisa Howley, Mary Donofrio, Anita Krishnan, Homa Ahmadzia, Stephanie Levasseur, Erin Paul, Sonal Owens, Kristopher Cumbermack, Jyothi Matta, Gary Joffe, Christopher Lindblade, Caitlin Haxel, Katherine Kohari, Joshua Copel, James Strainic, Tam Doan, Karla Bermudez‐Wagner, Conisha Holloman, Shreya S. Sheth, Stacy Killen, Theresa Tacy, Michelle Kaplinski, Lisa Hornberger, Philip M. Carlucci, Peter Izmirly, Nicola Fraser, Robert M. Clancy, Bettina F. Cuneo
Journal: Arthritis & Rheumatology (2023)

Objective This prospective study of pregnant patients, S urveillance To P revent AV B lock L ikely to O ccur Q uickly (STOP BLOQ), addresses the impact of anti‐SSA/Ro titers and utility of ambulatory monitoring in the detection of fetal second‐degree atrioventricular block (AVB). Methods Women with anti‐SSA/Ro autoantibodies by commercial testing were stratified into high and low anti–52‐kD and/or 60‐kD SSA/Ro titers applying at‐risk thresholds defined by previous evaluation of AVB pregnancies. The high‐titer group performed fetal heart rate and rhythm monitoring (FHRM) thrice daily and weekly/biweekly echocardiography from 17–26 weeks. Abnormal FHRM prompted urgent echocardiography to identify AVB. Results Anti–52‐kD and/or 60‐kD SSA/Ro met thresholds for monitoring in 261 of 413 participants (63%); for those, AVB frequency was 3.8%. No cases occurred with low titers. The incidence of AVB increased with higher levels, reaching 7.7% for those in the top quartile for anti–60‐kD SSA/Ro, which increased to 27.3% in those with a previous child who had AVB. Based on levels from 15 participants with paired samples from both an AVB and a non‐AVB pregnancy, healthy pregnancies were not explained by decreased titers. FHRM was considered abnormal in 45 of 30,920 recordings, 10 confirmed AVB by urgent echocardiogram, 7 being second‐degree AVB, all &lt;12 hours from normal FHRM and within another 0.75 to 4 hours to echocardiogram. The one participant with second/third‐degree and two participants with third‐degree AVB were diagnosed by urgent echocardiogram &gt;17 to 72 hours from an FHRM. Surveillance echocardiograms detected no AVB when the preceding interval FHRM recordings were normal. Conclusion High‐titer antibodies are associated with an increased incidence of AVB. Anti‐SSA/Ro titers remain stable over time and do not explain the discordant recurrence rates, suggesting that other factors are required. Fetal heart rate and rhythm (FHRM) with results confirmed by a pediatric cardiologist reliably detects conduction abnormalities, which may reduce the need for serial echocardiograms. image
Statistical learning quantifies transposable element-mediated cis-regulation
Authors: Cyril Pulver, Delphine Grun, Julien Duc, Shaoline Sheppard, Evarist Planet, Alexandre Coudray, Raphaël de Fondeville, Julien Pontis, Didier Trono
Journal: Genome biology (2023)

Transposable elements (TEs) have colonized the genomes of most metazoans, and many TE-embedded sequences function as cis-regulatory elements (CREs) for genes involved in a wide range of biological processes from early embryogenesis to innate immune responses. Because of their repetitive nature, TEs have the potential to form CRE platforms enabling the coordinated and genome-wide regulation of protein-coding genes by only a handful of trans-acting transcription factors (TFs).Here, we directly test this hypothesis through mathematical modeling and demonstrate that differences in expression at protein-coding genes alone are sufficient to estimate the magnitude and significance of TE-contributed cis-regulatory activities, even in contexts where TE-derived transcription fails to do so. We leverage hundreds of overexpression experiments and estimate that, overall, gene expression is influenced by TE-embedded CREs situated within approximately 500 kb of promoters. Focusing on the cis-regulatory potential of TEs within the gene regulatory network of human embryonic stem cells, we find that pluripotency-specific and evolutionarily young TE subfamilies can be reactivated by TFs involved in post-implantation embryogenesis. Finally, we show that TE subfamilies can be split into truly regulatorily active versus inactive fractions based on additional information such as matched epigenomic data, observing that TF binding may better predict TE cis-regulatory activity than differences in histone marks.Our results suggest that TE-embedded CREs contribute to gene regulation during and beyond gastrulation. On a methodological level, we provide a statistical tool that infers TE-dependent cis-regulation from RNA-seq data alone, thus facilitating the study of TEs in the next-generation sequencing era.
Mechanism of action of the bile acid receptor TGR5 in obesity
Authors: Weijun Lun, Qihao Yan, Xinghua Guo, Minchuan Zhou, Yan Bai, Jincan He, Hua Cao, Qishi Che, Jiao Guo, Zhengquan Su
Journal: Acta Pharmaceutica Sinica B (2023)

G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research.
Novel Prediction Equations for Absolute Risk Assessment of Total Cardiovascular Disease Incorporating Cardiovascular-Kidney-Metabolic Health: A Scientific Statement From the American Heart Association
Authors: Sadiya S. Khan, Josef Coresh, Michael J. Pencina, Chiadi E. Ndumele, Janani Rangaswami, Sheryl L. Chow, Latha P. Palaniappan, Laurence S. Sperling, Salim S. Virani, Jennifer E. Ho, Ian J. Neeland, Katherine R. Tuttle, Radhika Rajgopal Singh, Mitchell S.V. Elkind, Donald M. Lloyd-Jones
Journal: Circulation (2023)

Cardiovascular-kidney-metabolic (CKM) syndrome is a novel construct recently defined by the American Heart Association in response to the high prevalence of metabolic and kidney disease. Epidemiological data demonstrate higher absolute risk of both atherosclerotic cardiovascular disease (CVD) and heart failure as an individual progresses from CKM stage 0 to stage 3, but optimal strategies for risk assessment need to be refined. Absolute risk assessment with the goal to match type and intensity of interventions with predicted risk and expected treatment benefit remains the cornerstone of primary prevention. Given the growing number of therapies in our armamentarium that simultaneously address all 3 CKM axes, novel risk prediction equations are needed that incorporate predictors and outcomes relevant to the CKM context. This should also include social determinants of health, which are key upstream drivers of CVD, to more equitably estimate and address risk. This scientific statement summarizes the background, rationale, and clinical implications for the newly developed sex-specific, race-free risk equations: PREVENT (AHA Predicting Risk of CVD Events). The PREVENT equations enable 10- and 30-year risk estimates for total CVD (composite of atherosclerotic CVD and heart failure), include estimated glomerular filtration rate as a predictor, and adjust for competing risk of non-CVD death among adults 30 to 79 years of age. Additional models accommodate enhanced predictive utility with the addition of CKM factors when clinically indicated for measurement (urine albumin-to-creatinine ratio and hemoglobin A1c) or social determinants of health (social deprivation index) when available. Approaches to implement risk-based prevention using PREVENT across various settings are discussed.
CeO<sub>2</sub> Nanoparticles to Promote Wound Healing: A Systematic Review
Authors: Yijia Xue, Fan Yang, Likun Wu, Dandan Xia, Yunsong Liu
Journal: Advanced Healthcare Materials (2023)

Abstract Cerium (Ce) is a hot topic in the field of materials research due to its electronic layer structure and the unique antioxidant abilities of its oxide (CeO 2 ). Cerium oxide nanoparticles (CeO 2 NPs) demonstrate their potential as an antioxidant and antibacterial agent. Current research focuses on whether they can be used to promote wound healing and in what manner. This article provides a systematic review of the various forms of CeO 2 NPs that are used in wound‐healing materials over the past decade, as well as the effectiveness demonstrated by in vivo and in vitro experiments, with a focus on the relationship between concentration and effectiveness. CeO 2 NPs are expected to become effective ingredients in dressings that require antibacterial, antioxidant, and wound healing promoting properties. This article serves as a reference for further research and clinical applications of nano‐sized CeO 2 in wound healing.
Recovery of Therapeutically Ablated Engineered Blood‐Vessel Networks on a Plug‐and‐Play Platform
Authors: Lisa A. Krattiger, Lukas O. Moser, Rodi Odabasi, Adolfo Odriozola, Benjamin R. Simona, Valentin Djonov, Mark W. Tibbitt, Martin Ehrbar
Journal: Advanced Healthcare Materials (2023)

Limiting the availability of key angiogenesis-promoting factors is a successful strategy to ablate tumor-supplying blood vessels or to reduce excessive vasculature in diabetic retinopathy. However, the efficacy of such anti-angiogenic therapies (AATs) varies with tumor type, and regrowth of vessels is observed upon termination of treatment. The ability to understand and develop AATs remains limited by a lack of robust in vitro systems for modeling the recovery of vascular networks. Here, complex 3D micro-capillary networks are engineered by sequentially seeding human bone marrow-derived mesenchymal stromal cells and human umbilical vein endothelial cells (ECs) on a previously established, synthetic plug-and-play hydrogel platform. In the tightly interconnected vascular networks that form this way, the two cell types share a basement membrane-like layer and can be maintained for several days of co-culture. Pre-formed networks degrade in the presence of bevacizumab. Upon treatment termination, vessel structures grow back to their original positions after replenishment with new ECs, which also integrate into unperturbed established networks. The data suggest that this plug-and-play platform enables the screening of drugs with blood-vessel inhibiting functions. It is believed that this platform could be of particular interest in studying resistance or recovery mechanisms to AAT treatment.
Stem cell-based ischemic stroke therapy: Novel modifications and clinical challenges
Authors: Yuankai Sun, Xinchi Jiang, Jianqing Gao
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Ischemic stroke (IS) causes severe disability and high mortality worldwide. Stem cell (SC) therapy exhibits unique therapeutic potential for IS that differs from current treatments. SC's cell homing, differentiation and paracrine abilities give hope for neuroprotection. Recent studies on SC modification have enhanced therapeutic effects for IS, including gene transfection, nanoparticle modification, biomaterial modification and pretreatment. These methods improve survival rate, homing, neural differentiation, and paracrine abilities in ischemic areas. However, many problems must be resolved before SC therapy can be clinically applied. These issues include production quality and quantity, stability during transportation and storage, as well as usage regulations. Herein, we reviewed the brief pathogenesis of IS, the "multi-mechanism" advantages of SCs for treating IS, various SC modification methods, and SC therapy challenges. We aim to uncover the potential and overcome the challenges of using SCs for treating IS and convey innovative ideas for modifying SCs.
<scp>Single‐Cell</scp> Profiling of Bone Marrow B Cells and Early B Cell Developmental Disorders Associated With Systemic Lupus Erythematosus
Authors: Chen Dong, Yicheng Guo, Zechuan Chen, Teng Li, Juan Ji, Chi Sun, Jing Li, Haixia Cao, Yunfei Xia, Zhonghui Xue, Xixi Gu, Qian Liang, Rui Zhao, Ting Fu, Jiaqiang Ma, Shan Jiang, Chunmei Wu, Qiong Fu, Genkai Guo, Yanfeng Bao, Hua Guo, Junling Yang, Min Xu, Xiaoming Zhang, Zizhang Sheng, Zhifeng Gu
Journal: Arthritis & Rheumatology (2023)

The peripheral B cell compartment is heavily disturbed in systemic lupus erythematosus (SLE), but whether B cells develop aberrantly in the bone marrow (BM) is largely unknown.
Mepolizumab incompletely suppresses clinical flares in a pilot study of episodic angioedema with eosinophilia
Authors: Paneez Khoury, Michelle A. Makiya, Rodaba Rahim, Abbie Bowman, David Espinoza, Adam Schiffenbauer, Megan Koch, Charles Anderson, Gregory Constantine, Irina Maric, Xiaoping Sun, Stefania Pittaluga, Thomas Brown, JeanAnne M. Ware, Lauren Wetzler, Michael P. Fay, Amy D. Klion
Journal: Journal of Allergy and Clinical Immunology (2023)